Recent findings from this lab and others have demonstrated that backbone modifications render peptides more stable toward enzymatic degradation and often results in increased potency. For example a cyclic pentapeptide containing the psi (CH2S) amide replacement was nearly 10 times more potent than its amide parent in the mu selective guinea pig ileum assay. Most current effort is being directed as finding Mu, delta, or Kappa- selective analogs which regain oral activity. Yet our psi (CH2S) analogs proved to have potency toward both mu and delta receptors and, so far, oral activity has not been demonstrated. Since the specific modification sites and type are so critical to the resulting physical properties of the modified peptides, we propose an expanded study of enkephalin-related cyclic pseudopeptides based on such potent parents as the DiMair- Schiller mu-selective agonist, and the Hruby-Mosberg delta- selective DPDPE. Introduction of psi (CH2S) modifications directly by solid phase synthesis as well as preparation of more polar psi (CH2SO) and psi (CH2SO2) derivatives to probe the Schwyzer hypothesis are also among the objectives of the proposed study. By systemically exploring the changes caused by the peptide backbone modifications on enzymatic stability, transport, selectivity, conformation, and biological activity, it should be possible to design analogs that retain selectivity while processing enhanced metabolic stability and oral activity. In addition hybrid structures between cyclic enkephalins and the kappa-selective dynorphin derivatives will be prepared to test various models of receptor occupancy and selectivity.